Trial NCT04368728
Publication Polack F, N Engl J Med, 2020
Primary outcome on the report: Safety: The primary end points of this trial were solicited, specific local or systemic adverse events and use of antipyretic or pain medication within 7 days after the receipt of each dose … and unsolicited adverse events … through 1 month after the second dose and unsolicited serious adverse events through 6 months after the second dose. Efficacy: The first primary end point was the efficacy of BNT162b2 against confirmed Covid-19 with onset at least 7 days after the second dose in participants who had been without serologic or virologic evidence of SARS-CoV-2 infection up to 7 days after the second dose.

Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.

Bias Author's judgement Support for judgement
Randomization
Low 		Quote: "With the use of an interactive Web-based system, participants in the trial were randomly assigned in a 1:1 ratio to receive 30 ?g of BNT162b2 (0.3 ml volume per dose) or saline placebo." (published paper) "The responsibility of the unblinded dispenser and administrator must be assigned to an individual or individuals who will not participate in the evaluation of any study participants. Contact between the unblinded dispenser and study participants and unblinded administrator and study participants should be kept to a minimum. The remaining site personnel must not know study intervention assignments." (protocol)
Comment: Allocation sequence random. Allocation sequence concealed.
Minor imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: "study staff receiving, storing, dispensing, preparing, and administering the study interventions will be unblinded. All other study and site personnel, including the investigator, investigator staff, and participants, will be blinded to study intervention assignments." "syringes will be administered in a manner that prevents the study participants from identifying the study intervention type based on its appearance"
Comment: Study staff administering the interventions were not blinded. Participants and investigators were blinded.
As we are assessing the effect of assignment to intervention, the modified intention-to-treat analysis method performed on these outcomes, was considered appropriate.
Risk assessed to be low for outcomes: Severe COVID. Mortality. Adverse events. Withdrawals due to adverse events. Serious adverse events.

Per-protocol analysis was performed on the efficacy outcomes (as planned in the trial protocol).
As we are assessing the effect of assignment to intervention (intent-to-treat effect), this domain was evaluated as some concerns for this outcome.
Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID
Missing outcome data
Low 		Comment: 43,448 participants randomized; 43,252 participants analyzed for safety outcomes; 43,355 participants analyzed for efficacy outcomes.
Data available for >95% of population.
Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Severe Confirmed symptomatic COVID. All-cause mortality. Adverse events. Withdrawals due to adverse events. Serious adverse events.
Measurement of the outcome
Low 		Comment: Blinded study (outcome assessor).
Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Severe Confirmed symptomatic COVID. All-cause mortality. Adverse events. Withdrawals due to adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The protocol, statistical analysis plan, registry were available.
Results were not selected from multiple outcome measurements or analyses of the data.
Trial analyzed as pre-specified.
Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Severe Confirmed symptomatic COVID. All-cause mortality. Adverse events. Withdrawals due to adverse events. Serious adverse events.
Overall risk of bias
Some concerns